Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal

Abstract

Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms.

Keywords: atomoxetine; contextual extinction learning; fMRI; noradrenaline; renewal effect.

Figure 1

Predictive learning task. (A) Example of a trial during acquisition of the task. Participants learned to predict whether certain kinds of food, eaten in a certain restaurant, would cause a stomach ache or not. After an intertrial interval of 5–9 s the stimulus was presented in its context for 3 s, then a question was superimposed on the screen “Will the patient get a stomach ache?” for maximum 4 s response time. Feedback was shown for 2 s, providing the correct answer, e.g., “The patient does not have a stomach ache”. (B) Design of the predictive learning task. In condition AAA, extinction occurs in the same context as acquisition. In condition ABA, extinction occurs in a context different from that during acquisition. In both conditions, the final test for the renewal effect is performed in the context of acquisition. (C) Food images used as stimuli. Reprinted from Lissek et al. (2013) with permission from Elsevier.

Figure 2

Behavioral results. (A) Percentage of errors in extinction trials in the ATO (black) and PLAC (gray) groups. The ATO group made significantly less errors than the PLAC group over all extinction trials (overall), in extinction trials with consequence change only (overall cc), in ABA extinction trials with consequence change (ABA cc) and in AAA extinction trials with consequence change (AAA cc). (B) Extinction learning curves for ATO (black) and PLAC (gray) participants, with the extinction session divided into eight blocks of 10 trials each. During initial extinction in block 1, error rates did not differ between groups. However, in subsequent learning, the PLAC group was significantly slower in reducing errors during blocks 2–5. (C) Percent renewal effect responses in all participants (ABA all) and only in those participants who actually showed a renewal effect (ABA REN) in the ATO (black) and PLAC (gray) groups. ATO and PLAC groups did not differ with regard to the strength of the renewal effect they exhibited.

Figure 3

Top: Higher hippocampal activation in the ATO group compared to PLAC in the ABA condition (panel A) and the AAA condition (panel B) during extinction learning (red) and recall phase (blue). Two-sample t-tests ATO < PLAC thresholded at p < 0.01, minimum cluster size k = 10 voxel. Bottom: Higher vmPFC activation of ATO compared to PLAC in (A) extinction in a novel context (ABA condition)—righthemispheric BA 10, peak MNI coordinate 35 48 −4; and in (B) extinction in the familiar context (AAA condition)—lefthemispheric BA 10, peak MNI coordinate −2 64 10. Two-sample t-tests ATO < PLAC thresholded at p < 0.01.